This invention is directed to [di(ether or thioether)heteroaryl or fluoro substituted aryl] compounds, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states associated with proteins that mediate cellular activity.
Disease states associated with abnormally high physiological levels of cytokines such as TNF are treatable according to the invention. TNF is an important pro-inflammatory cytokine which causes hemorrhagic necrosis of tumors and possesses other important biological activities. TNF is released by activated macrophages, activated T-lymphocytes, natural killer cells, mast cells and basophils, fibroblasts, endothelial cells and brain astrocytes among other cells.
The principal in vivo actions of TNF can be broadly classified as inflammatory and catabolic. It has been implicated as a mediator of endotoxic shock, inflammation of joints and of the airways, immune deficiency states, allograft rejection, and in the cachexia associated with malignant disease and some parasitic infections. In view of the association of high serum levels of TNF with poor prognosis in sepsis, graft versus host disease and acute respiratory distress syndrome, and its role in many other immunological processes, this factor is regarded as an important mediator of general inflammation.
TNF primes or activates neutrophils, eosinophils, fibroblasts and endothelial cells to release tissue damaging mediators. TNF also activates monocytes, macrophages and T-lymphocytes to cause the production of colony stimulating factors and other pro-inflammatory cytokines such IL1, IL6, IL8 and GM-CSF, which in some case mediate the end effects of TNF. The ability of TNF to activate T-lymphocytes, monocytes, macrophages and related cells has been implicated in the progression of Human Immunodeficiency Virus (HIV) infection. In order for these cells to become infected with HIV and for HIV replication to take place the cells must be maintained in an activated state. Cytokines such as TNF have been shown to activate HIV replication in monocytes and macrophages. Features of endotoxic shock such as fever, metabolic acidosis, hypotension and intravascular coagulation are thought to be mediated through the actions of TNF on the hypothalamus and in reducing the anti-coagulant activity of vascular endothelial cells. The cachexia associated with certain disease states is mediated through indirect effects on protein catabolism. TNF also promotes bone resorption and acute phase protein synthesis.
The discussion herein related to disease states associated with TNF include those disease states related to the production of TNF itself, and disease states associated with other cytokines, such as but not limited to IL-1, or IL-6, that are modulated by association with TNF. For example, an IL-1 associated disease state, where IL-1 production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state associated with TNF. TNF-alpha and TNF-beta are also herein referred to collectively as xe2x80x9cTNFxe2x80x9d unless specifically delineated otherwise, since there is a close structural homology between TNF-alpha (cachectin) and TNF-beta (lymphotoxin) and each of them has a capacity to induce similar biologic responses and bind to the same cellular receptor.
Disease states associated with pathological conditions that are modulated by inhibiting enzymes, which are associated with secondary cellular messengers, such as cyclic AMP phosphodiesterase, are also treatable according to the invention Cyclic AMP phosphodiesterase is an important enzyme which regulates cyclic AMP levels and in turn thereby regulates other important biological reactions. The ability to regulate cyclic AMP phosphodiesterase, including type IV cyclic AMP phosphodiesterase, therefore, has been implicated as being capable of treating assorted biological conditions.
In particular, inhibitors of type IV cyclic AMP phosphodiesterase have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and of the function of eosinophils, and for treating other diseases and conditions characterized by, or having an etiology involving, morbid eosinophil accumulation. Inhibitors of cyclic AMP phosphodiesterase are also implicated in treating inflammatory diseases, proliferative skin diseases and conditions associated with cerebral metabolic inhibition.
Chemical Abstracts, 108(15), Apr. 11, 1988, abstract no. 131583p pertains to an abstract of Japanese Patent Application Publication No. JP-A-62 158,253 which discloses that a substituted phenyl compound of formula 
is a cardiotonic, but does not disclose or suggest that the compound inhibits cyclic AMP phosphodiesterase or TNF. JP-A-62 158,253 also does not disclose or suggest that the moiety that is ortho to R1 may be anything other than benzyloxy. JP-A-62 158,253 furthermore does not disclose compounds wherein a methine (xe2x95x90CHxe2x80x94) moiety of the phenyl moiety of the benzamido moiety is substituted by a halomethine (xe2x95x90CXxe2x80x94; wherein X is a halo atom) moiety or an imine (xe2x95x90Nxe2x80x94) moiety.
Chemical Abstracts, 99(6), Aug. 8, 1983, abstract no. 43556z pertains to an abstract of Japanese Patent Application Publication No. JP-A-5 869,812 which discloses that a phenyl compound of formula 
is a hypoglycemic agent, but does not disclose or suggest that the compound inhibits cyclic AMP phosphodiesterase or TNF. JP-A-5 869,812 also does not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
Panos Grammaticakis, Bull. Soc. Chim. Fr., 848-857 (1965) discloses a phenyl compound of the formula 
Grammaticakis examines the ultraviolet and visible absorbances of compounds bearing different substituents. Grammaticakis does not disclose or suggest that the compound exhibits any pharmacological activity. JP-A-5 869,812 also does not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
Ian W. Mathison, et al., J. Med. Chem., 16(4), 332-336 (1973), discloses that a phenyl compound of formula 
is a hypotensive agent, but do not disclose or suggest that the compound inhibits cyclic AMP phosphodiesterase or TNF. Mathison, et al., also do not disclose or suggest that the benzamido moiety may be substituted by anything other than methoxy.
European Patent Application Publication No. EP 232199 B1 discloses hat phenyl compounds of formula 
wherein R2 is alkyl or mono- or polycyclic cycloalkyl, exhibit anti-inflammatory and/or anti-allergic activity. EP 232199 B1 does not disclose or suggest compounds wherein the R2 substituent is bonded to the phenyl moiety via an oxygen or sulfur atom. EP 232199 B1 furthermore does not disclose compounds wherein a methine moiety of the phenyl moiety of the benzamido moiety is substituted by a halomethine moiety or an imine moiety.
European Patent Application Publication No. EP 470,805 A1 discloses phenyl compounds of the formula 
wherein R may be C3-7 alkyl, C3-7 cycloalkyl or 
Z may be a bond; o is 1-4; a and b are independently 1-3; and c is 0-2. EP 470,805 A1 discloses that these compounds are useful intermediates for preparing PDE IV inhibitors, but does not disclose or suggest that the compounds have any pharmacological activity. EP 470,805 A1 furthermore does not disclose compounds wherein a methine moiety of the phenyl moiety of the phenylacyl moiety is substituted by a halomethine moiety or an imine moiety.
Japanese Patent Application Publication No. JP-A-0 4360847 discloses compounds of the formula 
wherein R1, R2 and R3 may be the same or different and may be halo or lower alkoxy or lower alkyl both optionally substituted by halo; and A may be optionally substituted aryl or 5-6 membered heterocyclyl group. JP-A-0 4360847 discloses that the compounds are useful intermediates for preparing antimicrobial agents, but does not disclose or suggest that the compounds have any pharmacological activity. JP-A-0 4360847 also does not disclose that the compounds wherein the phenylacyl moiety is substituted in the 3,4 positions relative to the acyl moiety by lower alkoxy groups and has a methine moiety of the phenyl moiety substituted by a halomethine moiety or an imine moiety.
WO Patent Application No. 92/12961 discloses that compounds of the formula 
inhibit cyclic AMP phosphodiesterase. WO Patent Application No. 92/12961 does not disclose or suggest that these compound inhibit TNF. WO Patent Application No. 92/12961 also does not disclose compounds wherein a methine moiety of the diether phenyl moiety is substituted by a halomethine moiety or an imine moiety.
WO Patent Application No. 93/25517 discloses that compounds of the following formula inhibit PDE IV. WO Patent Application No. 93/25517 does 
not disclose or suggest that these compound inhibit TNF. WO Patent Application No. 93/25517 also does not disclose compounds wherein a methine moiety of the diether phenyl moiety is substituted by a halomethine moiety or an imine moiety.
WO Patent Application No. 93/10228 discloses that compounds of the following formula inhibit PDE IV and as such are useful in treatment of inflammatory diseases. WO Patent Application No. 93/10228 does not disclose or suggest 
that these compounds inhibit TNF. WO Patent Application No. 93/10228 also does not disclose compounds wherein a methine moiety of the diether phenyl moiety is substituted by a halomethine moiety or an imine moiety.
WO Patent Application No. 93/07111 discloses that compounds of the following formula wherein X may be YR2; Y is O or S(O)m; X3 is halogen or 
hydrogen; and A is a group of formula 
inhibit PDE IV. WO Patent Application No. 93/07111 does not disclose or suggest compounds wherein the A substituent is a [(xe2x80x94CXNHxe2x80x94 or xe2x80x94CXCH2xe2x80x94)aryl or heteroaryl] moiety wherein X is O or S.
WO Patent Application No. 91/16303 discloses that compounds of the following formula wherein R1, R2 and R3 may be hydrogen, halogen, lower alkyl, 
lower alkoxy or cycloalkoxy inhibit PDE IV. WO Patent Application No. 91/16303 does not disclose or suggest compounds wherein the lactam moiety is substituted by a [(xe2x80x94CXNHxe2x80x94 or xe2x80x94CXCH2xe2x80x94)aryl or heteroaryl] moiety wherein X is O or S.
WO Patent Application No. 92/19594 discloses that compounds of the following formula wherein X may be YR2; Y is O or S(O)m; and X3 may be 
hydrogen or halogen inhibit PDE IV. WO Patent Application No. 92/19594 does not disclose or suggest compounds wherein the lactam moiety is substituted by a [(xe2x80x94CXNHxe2x80x94 or xe2x80x94CXCH2xe2x80x94)aryl or heteroaryl] moiety wherein X is O or S.
This invention is directed to a compound of formula I, which is useful for inhibiting the production or physiological effects of TNF in the treatment of a patient suffering from a disease state associated with a physiologically detrimental excess of tumor necrosis factor (TNF), where formula I is as follows: 
wherein
R1 is lower alkyl optionally substituted by one or more of halo, cycloalkyl or cycloalkenyl;
R2 is alkyl, alkenyl or alkynyl each optionally substituted by one or more of halo, cycloalkyl or cycloalkenyl; or cycloalkyl or cycloalkenyl each optionally substituted by one or more of halo, methylidene or alkyl; or optionally substituted cyclothioalkyl consisting of a non-aromatic monocyclic or multicyclic ring system of 3 to about 10 ring atoms wherein at least one of the ring atoms is sulphur and the other ring atoms are carbon and the substituted cyclothioalkyl is substituted by one or more halo, or any ring sulphur atom is optionally oxidised to the corresponding S-oxide or S,S-dioxide; or optionally substituted cyclothioalkenyl consisting of a non-aromatic monocyclic or multicyclic ring system of 3 to about 10 ring atoms wherein at least one of the ring atoms is sulphur, the other ring atoms are carbon and the ring system contains a carbon-carbon double bond and the substituted cyclothioalkenyl is substituted by one or more halo or any ring sulphur atoms is optionally oxidised to the corresponding S-oxide or S,S-dioxide;
R3 is optionally substituted aryl or heteroaryl, wherein the substituted aryl or substituted heteroaryl group is substituted by one or more substituents which may be the same or different and are selected from alkyl, aryl, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkyloxy, carboxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarboxyl, aryloxycarbonyl, aralkyloxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, aralkylthio, Y1Y2Nxe2x80x94, Y1Y2NCOxe2x80x94 or Y1Y2NSO2xe2x80x94, where Y1 and Y2 are independently hydrogen, alkyl, aryl, and aralkyl;
Q1, Q2 and Q3 are independently nitrogen, CX or CH, provided that at least one of Q1, Q2 and Q3 is other than CH;
Z, Z1 and Z2 are independently oxygen or sulfur;
Z3 is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CZCH2xe2x80x94, xe2x80x94CZxe2x80x94CZxe2x80x94, xe2x80x94CH2xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94CX2xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94SO2xe2x80x94 or xe2x80x94CZNHxe2x80x94; and
X is halo;
or N-oxide thereof or a pharmaceutically acceptable salt thereof; with the proviso that R1Z1 and R2Z2 cannot both represent methoxy.
Compounds within the scope of the present invention also inhibit cyclic AMP phosphodiesterase, and are useful in treating a disease state associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase, such disease states including inflammatory and autoimmune diseases, in particular type IV cyclic AMP phosphodiesterase. The present invention is therefore directed to their pharmacological use, pharmacological compositions comprising the compounds and methods for their preparation.
As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
xe2x80x9cPatientxe2x80x9d includes both human and other mammals.
xe2x80x9cAlkylxe2x80x9d means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 15 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. xe2x80x9cLower alkylxe2x80x9d means about 1 to about 4 carbon atoms in the chain which may be straight or branched. The alkyl group is optionally substituted by one or more of halo, cycloalkyl or cycloalkenyl groups. Exemplary alkyl groups include methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl; preferred are methyl, difluoromethyl and i-propyl.
xe2x80x9cAlkenylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkenyl chain. xe2x80x9cLower alkenylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkenyl group is optionally substituted by one or more halo, cycloalkyl or cycloalkenyl. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and decenyl.
xe2x80x9cAlkynylxe2x80x9d means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched having about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkynyl chain. xe2x80x9cLower alkynylxe2x80x9d means about 2 to about 4 carbon atoms in the chain which may be straight or branched. The alkynyl group is optionally substituted by one or more halo, cycloalkyl or cycloalkenyl. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.
xe2x80x9cCycloalkylxe2x80x9d means a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. The cycloalkyl group is optionally substituted by one or more halo, methylidene (H2Cxe2x95x90) or alkyl. Exemplary monocyclic cycloalkyl rings include cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl; more preferred is cyclopentyl. Exemplary multicyclic cycloalkyl rings include 1-decalin, adamant-(1- or 2-)yl, trinorbornyl and tricyclo[2.2.1.02.6.]heptyl.
xe2x80x9cCycloalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system containing a carbon-carbon double bond and having about 3 to about 10 carbon atoms. The cycloalkenyl group is optionally substituted by one or more halo, alkyl and methylidene (CH2xe2x95x90). Preferred monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl; more preferred is cyclopentenyl. A preferred multicyclic cycloalkenyl ring is a norbornylenyl.
xe2x80x9cCyclothioalkylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 ring atoms wherein at least one of the ring atoms is sulfur and the other ring atoms are carbon. Preferred rings include about 5 to about 6 ring atoms. Also preferred are rings in which one or two of the ring atoms is/are sulfur. The cyclothioalkyl is optionally substituted by one or more halo. The thio moiety of the cyclothioalkyl ring may also be optionally oxidized to the corresponding S-oxide or S,S-dioxide. Preferred monocyclic cyclothioalkyl rings include tetrahydrothiophenyl and tetrahydrothiopyranyl; more preferred is tetrahydrothiophenyl.
xe2x80x9cCyclothioalkenylxe2x80x9d means a non-aromatic monocyclic or multicyclic ring system having about 3 to about 10 ring atoms wherein at least one of the ring atoms is sulfur and the other ring atoms are carbon and the ring system contains a carbon-carbon double bond. Preferred rings include about 5 to about 6 ring atoms. Also preferred are rings in which one or two of the ring atoms is/are sulfur. The cyclothioalkenyl is optionally substituted by one or more halo. The thio moiety of the cyclothioalkenyl may also be optionally oxidized to the corresponding S-oxide or S,S-dioxide. Preferred monocyclic cyclothioalkyl rings include dihydrothiophenyl and dihydrothiopyranyl; more preferred is dihydrothiophenyl.
xe2x80x9cAromaticxe2x80x9d means aryl or heteroaryl as defined below. Preferred aromatic groups include phenyl, halo substituted phenyl and azaheteroaryl.
xe2x80x9cArylxe2x80x9d means aromatic carbocyclic radical containing about 6 to about 10 carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl or naphthyl substituted with one or more aryl group substituents which may be the same or different, where xe2x80x9caryl group substituentxe2x80x9d includes hydrogen, alkyl, aryl, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkyloxy, carboxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, acylamino, aroylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, aralkylthio, Y1Y2Nxe2x80x94, Y1Y2NCOxe2x80x94 or Y1Y2NSO2xe2x80x94, where Y1 and Y2 are independently hydrogen, alkyl, aryl, and aralkyl. Preferred aryl group substituents include hydrogen, alkyl, hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino, alkylthio, Y3Y4Nxe2x80x94, Y3Y4NCOxe2x80x94 and Y3Y4NSO2xe2x80x94, where Y3 and Y4 are independently hydrogen and alkyl.
xe2x80x9cHeteroarylxe2x80x9d means about a 5- to about a 10-membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the carbon atoms in the ring system is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. The heteroaryl may also be substituted by one or more aryl group substituents. xe2x80x9cAzaheteroarylxe2x80x9d means a subclass of heteroaryl wherein one or more of the atoms in the ring system is/are replaced by nitrogen. Imine nitrogen moieties of an azaheteroaryl group may also be in an oxidized state such as the corresponding N-oxide. Exemplary heteroaryl groups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, pyridazinyl, 1,2,4-triazinyl, quinolinyl, and isoquinolinyl. Preferred heteroaryl groups include pyrazinyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl and isothiazolyl. Preferred azaheteroaryl groups include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or 1,2,4-triazinyl.
xe2x80x9cAralkylxe2x80x9d means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthlenemethyl.
xe2x80x9cHydroxyalkylxe2x80x9d means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Exemplary hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
xe2x80x9cAcylxe2x80x9d means an Hxe2x80x94COxe2x80x94 or alkyl-COxe2x80x94 group in which the alkyl group is as previously described. Preferred acyls contain a lower alkyl. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and palmitoyl.
xe2x80x9cAroylxe2x80x9d means an aryl-COxe2x80x94 group in which the aryl group is as previously described. Exemplary groups include benzoyl and 1- and 2-naphthoyl.
xe2x80x9cAlkoxyxe2x80x9d means an alkyl-Oxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and heptoxy.
xe2x80x9cAryloxyxe2x80x9d means an aryl-Oxe2x80x94 group in which the aryl group is as previously described. Exemplary aryloxy groups include phenoxy and naphthoxy.
xe2x80x9cAralkyloxyxe2x80x9d means an aralkyl-Oxe2x80x94 group in which the aralkyl groups is as previously described. Exemplary aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
xe2x80x9cAlkylthioxe2x80x9d means an alkyl-Sxe2x80x94 group in which the alkyl group is as previously described. Exemplary alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio.
xe2x80x9cArylthioxe2x80x9d means an aryl-Sxe2x80x94 group in which the aryl group is as previously described. Exemplary arylthio groups include phenylthio and naphthylthio.
xe2x80x9cAralkylthioxe2x80x9d means an aralkyl-Sxe2x80x94 group in which the aralkyl group is as previously described. An exemplary aralkylthio group is benzylthio.
xe2x80x9cY3Y4Nxe2x80x94xe2x80x9d means a substituted or unsubstituted amino group, wherein Y3 and Y4 are as previously described. Exemplary groups include amino (H2Nxe2x80x94), methylamino, ethylmethylamino, dimethylamino and diethylamino.
xe2x80x9cAlkoxycarbonylxe2x80x9d means an alkylxe2x80x94O-COxe2x80x94 group. Exemplary alkoxycarbonyl groups include methoxy- and ethoxycarbonyl.
xe2x80x9cAryloxycarbonylxe2x80x9d means an aryl-Oxe2x80x94COxe2x80x94 group. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxycarbonyl.
xe2x80x9cAralkyloxycarbonylxe2x80x9d means an aralkylxe2x80x94O-COxe2x80x94 group. An exemplary aralkyloxycarbonyl group is benzyloxycarbonyl.
xe2x80x9cY1Y2NCOxe2x80x94xe2x80x9d means a substituted or unsubstituted carbamoyl group, wherein Y1 and Y2 are as previously described. Exemplary groups are carbamoyl (H2NCOxe2x80x94) and dimethylcarbamoyl (Me2NCOxe2x80x94).
xe2x80x9cY1Y2NSO2xe2x80x94xe2x80x9d means a substituted or unsubstituted sulfamoyl group, wherein Y1 and Y2 are as previously described. Exemplary groups are sulfamoyl (H2NSO2xe2x80x94) and dimethylsulfamoyl (Me2NSO2xe2x80x94).
xe2x80x9cAcylaminoxe2x80x9d is an acyl-NHxe2x80x94 group wherein acyl is as defined herein.
xe2x80x9cAroylaminoxe2x80x9d is an aroyl-NHxe2x80x94 group wherein aroyl is as defined herein.
xe2x80x9cAlkylsulfonylxe2x80x9d means an alkyl-SO2xe2x80x94 group. Preferred groups are those in which the alkyl group is lower alkyl.
xe2x80x9cAlkylsulfinylxe2x80x9d means an alkyl-SOxe2x80x94 group. Preferred groups are those in which the alkyl group is lower alkyl.
xe2x80x9cArylsulfonylxe2x80x9d means an aryl-SO2xe2x80x94 group.
xe2x80x9cArylsulfinylxe2x80x9d means an aryl-SOxe2x80x94 group.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo. Preferred are fluoro, chloro or bromo; more preferred are fluoro or chloro, and further preferred is fluoro.
xe2x80x9cN-oxidexe2x80x9d means a moiety of the following structure 
A compound of formula I is preferred for use in treating a disease state associated with a physiologically detrimental excess of tumor necrosis factor. Disease states associated with pathological conditions that are modulated by inhibiting tumor necrosis factor are treatable with a compound of formula I.
A compound of formula I is also preferred for use in treating a disease state associated with a physiologically detrimental excess of cyclic AMP phosphodiesterase. Disease states associated with pathological conditions that are modulated by inhibiting cyclic AMP phosphodiesterase are treatable with a compound of formula I.
According to a compound aspect of the invention, preferred compounds are described formula I,
wherein
R2 is alkyl, cycloalkyl, cycloalkenyl or cyclothioalkyl;
R3 is phenyl, substituted phenyl or azaheteroaryl;
Q1 and Q2 are independently nitrogen, CX or CH, and at least one of Q1 and Q2 is other than CH;
Q3 is CH; and
Z3 is xe2x80x94CZCH2xe2x80x94 or xe2x80x94CZNHxe2x80x94.
According to a further compound aspect of the invention, preferred compounds are described formula I,
wherein
R1 is methyl or difluoromethyl;
R2 is isopropyl, cyclopropylmethyl, cyclopentyl, trinorbornyl, trinorbornenyl, tricyclo[2.2.1.02.6]heptanyl and tetrahydrothiophenyl;
Q3 is CH;
Z1 is oxygen or sulphur;
Z2 is oxygen; and
Z3 is xe2x80x94COCH2xe2x80x94 or xe2x80x94CONHxe2x80x94.
According to another aspect of the invention, more preferred compounds of formula I are described wherein Q1 and Q2 are independently nitrogen, CX or CH, and at least one of Q1 and Q2 is nitrogen or CX, and Q3 is CH. Also preferred are compounds of the invention wherein Q1 is CX, and Q2 and Q3 are CH; Q2 is CX, and Q1 and Q3 are CH; Q1 is N, and Q2 and Q3 are CH; Q2 is N, and Q1 and Q3 are CH; Q1 and Q2 are CH, and Q3 are N; and Q1 and Q2 are N, and Q3 are CH. CX is preferably CF. Further preferred are compounds wherein Q2 is nitrogen or CF.
According to a further aspect of the invention, preferred are N-oxide compounds of formula 1, that is compounds of formula I wherein independently Q1, Q2 or Q3 is N-oxide and/or R3 is azaheterocyclyl having an imine moiety thereof as an N-oxide. Futher preferred are compounds of formula I wherein Q1 and Q3 are CH, and Q2 is an N-oxide. Also futher preferred are compounds of formula I wherein R3 is 3,5-dihalo-1-oxido-4-pyridinium.
Compounds of the invention wherein R1 is lower alkyl optionally substituted by one or more halo, preferably fluoro, are also preferred. Compounds of the invention wherein R2 is substituted by one or more halo, preferably fluoro, are also preferred. It is further preferred that the halo substitution is on a position of R1 or R2 that is attached respectively to Z1 and Z2. Where R2 is cyclothioalkyl or cyclothioalkenyl substituted by halo, it is also preferred that the halo substitution is on a position adjacent to the thio moiety of the cyclothioalkyl or cyclothioalkenyl.
Among the compounds of the invention wherein R3 is substituted phenyl, the phenyl group is preferably substituted on the 2-position or on both the 2- and 6-positions; more preferably on both the 2- and 6-positions. It is also preferred that the phenyl substituent is halo; preferably chloro or fluoro.
Similarly, among compounds of the invention where R3 is substituted heteroaryl, the heteroaryl group is preferably substituted on one or both, more preferably on both, of the positions adjacent to a position of R3 that is attached to Z3.
Special embodiments of the compounds of the invention include those of formula I wherein R3 is azaheteroaryl substituted on one or both, more preferably on both, of the positions adjacent to a position of R3 that is attached to Z3, or an N-oxide thereof. Further preferred are compounds wherein R3 is a 3,5-dihalopyrid-4-yl moiety, preferably wherein halo is chloro or fluoro, or an N-oxide thereof.
Special embodiments of the compounds of the invention also include those of formula I wherein Z3 is xe2x80x94CZNHxe2x80x94 or xe2x80x94CZCH2xe2x80x94, more preferably wherein Z is oxygen.
Special embodiments of the compounds of the present invention include those wherein R2 is isopropyl, cyclopropylmethyl, cyclopentyl, trinorbornyl, trinorbornenyl, tricyclo[2.2.1.02.6.]heptanyl and tetrahydrothiophenyl.
Another special embodiment of the compounds of the invention include those of formula I wherein R1 is lower alkyl optionally substituted by halo, preferably fluoro; and R2 is isopropyl, cyclopropylmethyl, cyclopentyl, trinorbornyl, trinorbornenyl, tricyclo[2.2.1.02.6.]heptanyl and tetrahydrothiophenyl.
According to a further aspect of the invention, preferred compounds of mula I are described wherein Z1 and Z2 are oxygen, and Z1 is sulfur and Z2 oxygen are preferred. More preferred are where Z1 and Z2 are oxygen.
Preferred compounds for use according to the invention are selected om the following:
A N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
B N-(2,6-difluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
C N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
D N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
E N-(2,4,6-trichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
F N-(2,6-dibromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
G N-(2-chloro-6-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
H N-(2,6-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
I N-(2-fluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
J N-phenyl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
K N-(2-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
L N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
M N-(3-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
N N-(4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
O N-(2,6-dimethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
P N-(2-methylthiophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
Q N-(2-bromophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
R N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
S N-(2-aminosulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
T N-(2-benzoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
U N-(2-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
V N-(2,5-dichlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
W N-(3-methylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
X N-(2-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
Y N-(2-dimethylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
Z N-(2-acetylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AA N-(2-hydroxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AB N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AC N-pyrid-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AD N-pyrazin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AE N-pyrimidin-2-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AF N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AG N-pyrid-3-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AH N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AI N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AJ N-pyrid-4-yl-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AK N-(3,5-dimethylisoxazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AL N-(3,5-dibromopyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AM N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AN N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AO N-(2,6-dichloro-4-methoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AP N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AQ N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AR N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AS N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
T N-(3-bromo-5-chloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AU N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AV N-(2,6-dichloro-4-methoxyphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AW N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AX N-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AY N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
AZ N-(5-cyano-3-methylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BA N-(2,6-dichloro-4-carbamoylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BB N-(3-ch loro-2,5,6-trifluoropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BC N-(4-nitrophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BD N-(3-methyl-5-bromoisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BE N-(3,5-dimethylisothiazol-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BF N-(2,6-difluorophenyl)-3-cyclohexyloxy-6-fluoro-4-methoxybenzamide;
BG N-(2,6-difluorophenyl)-3-butoxy-6-fluoro-4-methoxybenzamide;
BH N-(2,6-difluorophenyl)-3-propoxy-6-fluoro-4-methoxybenzamide;
BJ N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-6-fluoro-4-methoxybenzamide;
BL N-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-6-fluoro-4-methoxybenzamide;
BN N-(2-methylsulfonylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BP N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide);
BR N-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide);
BT N-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-6-fluoro-4-methoxy(thiobenzamide);
BV N-(2,6-dichloro-4-acetylaminophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BX N-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
BZ N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
CB sodium salt of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
CC (xc2x1)N-(3,5-dichloropyrid-4-yl)-3-exonorbornyloxy-6-fluoro-4-methoxybenzamide;
CD N-(3,5-dichloropyrid-4-yl)-2-fluoro-5-isopropyloxy-4-methoxybenzamide;
CE (xc2x1)N-(3,5-dichloropyrid-4-yl)-2-fluoro-4-methoxy-5-(tricyclo[2.2.1.0]hept-2-yloxy)benzamide hemihydrate;
CF N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzamide
CG N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-2-fluoro-5-isopropyloxybenzamide;
CH 2-(3,5-dichloropyrid-4-yl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanone;
CI N-(3,5-dichloro-1-oxido-4-pyridinio)-2-fluoro-5-isopropyloxy-4-methoxybenzamide;
CJ (xc2x1)N-(3,5-dichloro-1-oxido-4-pyridinio)-3-exo-(8,9,10-trinorbornyloxy)-6-fluoro-4-methoxybenzamide;
CK N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-6-fluoro-4-methoxybenzamide;
CL N-(3,5-dichloro-1-oxido-4-pyridinio)-3-cyclopentyloxy-4-difluoromethoxy-6-fluorobenzamide;
CM N-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxy-2-fluoro-5-isopropyloxybenzamide;
CN 2-(3,5-Dichloro-1-oxido-4-pyridinio)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethanone;
CO 5-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-6-methoxynicotinamide;
CP N-(2,6-dichlorophenyl)-5-cyclopentyloxy-6-methoxynicotinamide;
CQ 5-cyclopentyloxy-N-(3,5-dimethylisoxazol-4-yl)-6-methoxynicotinamide
CR 5-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-6-methoxynicotinamide
CS 6-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-5-methoxypyridine-2-carboxamide;
CT 1-(5-cyclopentyloxy-6-methoxypyridin-3-yl)-2-(3,5-dichloropyrid-4-yl)ethanone;
CU 5-cyclopentyloxy-N-(3,5-dichloro-4-pyridyl)-6-methylthionicotinamide;
CV N-(3,5-dichloro-4-pyridyl)-5-isopropyloxy-6-methylthionicotinamide;
CW 2-(3,5-dichloro-4-pyridyl)-1-(5-isopropyloxy-6-methylthio-3-pyridyl)ethanone;
CX 1-(5-cyclopentyloxy-6-methoxypyrid-3-yl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone hemihydrate;
CY (xc2x1)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-exo-(8,9,10-trinorborn-5-en-2-yloxy)nicotinamide;
CZ (xc2x1)-N-(3,5-dichloropyrid-4-yl)-6-methoxy-5-(tricyclo[2.2.1.0.2.6.]hept-2-yloxy)nicotinamide monohydrate;
DA N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DB N-(2,6-difluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DC N-(2-chloro-6-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DD N-(2-trifluoromethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DE N-(2,4,6-trichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DF N-(2,6-dibromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DG N-(2-chloro-6-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DH N-(2,6-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DI N-(2-fluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DJ N-phenyl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DK N-(2-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DL N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DM N-(3-chlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DN N-(4-methoxyphenyl)-4-cyclopentyloxy-5-m ethoxypyridine-2-carboxamide;
DO N-(2,6-dimethylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DP N-(2-methylthiophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DQ N-(2-bromophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DR N-(2-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DS N-(2-aminosulfonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DT N-(2-benzoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DU N-(2-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DV N-(2,5-dichlorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DW N-(3-methylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DX N-(2-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DY N-(2-dimethylaminophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
DZ N-(2-acetylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EA N-(2-hydroxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EB N-(4-chloropyrid-3-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EC N-pyrid-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
ED N-pyrazin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EE N-pyrimidin-2-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EF N-(3-methylpyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EG N-pyrid-3-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EH N-(3-chloropyrid-2-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EI N-(3-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EJ N-pyrid-4-yl-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EK N-(3,5-dimethylisoxazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EL N-(3,5-dibromopyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EM N-(3,5-dimethylpyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EN N-(2,6-dichloro-4-cyanophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EO N-(2,6-dichloro-4-methoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EP N-(2,3,5-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EQ N-(2,6-dichloro-4-ethoxycarbonylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
ER N-(2,6-dichloro-4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
ES N-(3,5-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
ET N-(3-bromo-5-chloropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EU N-(2,4,6-trifluorophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EV N-(2,6-dichloro-4-methoxyphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EW N-(4,6-dichloropyrimid-5-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EX N-(2,3,5,6-tetrafluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EY N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
EZ N-(5-cyano-3-methylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
FA N-(2,6-dichloro-4-carbamoylphenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
FB N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
FC N-(4-nitrophenyl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
FD N-(3-methyl-5-bromoisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
FE N-(3,5-dimethylisothiazol-4-yl)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
FF N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxypyridine-2-carboxamide;
FG 1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone;
FH (xc2x1)-N-(3,5-difluoropyrid-4-yl)-6-methoxy-5-exo(8,9,10-trinorborn-2-yloxy)nicotinamide;
FI (xc2x1)-N-(3,5-dichloropyridin-4-yl)-6-methoxy-5-exo(8,9,10-trinorborn-2-yloxy)nicotinamide;
FJ (xc2x1)-N-(3,5-dichloropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0.2.6.]hept-2-yloxy)pyridine-2-carboxamide;
FK (xc2x1)-N-(3,5-difluoropyrid-4-yl)-5-methoxy-4-(tricyclo[2.2.1.0.2.6.]hept-2-yloxy)pyridine-2-carboxamide hydrate;
FL (xc2x1)-N-(3,5-dichloropyridin-4-yl)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxamide;
FM N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamide;
FN N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-methoxypyridine-2-carboxamide;
FO (xc2x1)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0.2.6.]-hept-2-yloxy)pyridine-2-carboxamide;
FP (xc2x1)-N-(3,5-difluoro-1-oxido-4-pyridinio)-5-methoxy-4-(tricyclo[2.2.1.0.2.6.]-hept-2-yloxy)pyridine-2-carboxamide;
FQ N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxypyridine-2-carboxamide;
FR N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxypyridine-2-carboxamide hemihydrate;
FS (xc2x1)-N-(3,5-dichloro-1-oxido-4-pyridinio)-5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridine-2-carboxamide;
FT N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide;
FU N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridinium-2-carboxamide;
FV N-(3,5-dichloro-1-oxido-4-pyridinio)-4-isopropyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide; FW 1-(5-methoxy-4-(tricyclo[2.2.1.0.2.6.]hept-2-yloxy)pyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone;
FX (xc2x1)-1-(5-methoxy-4-(tetrahydrothiophen-3-yloxy)pyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone;
FY 1-(4-(tricyclo[2.2.1.0.2.6.]hept-2-yloxy)-5-methoxypyridin-2-yl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone;
FZ N-(3,5-dichloropyridin-4-yl)-4-cyclopropylmethoxy-5-methoxy-1-oxidopyridinium-2-carboxamide;
GA N-(3,5-dichloropyridin-4-yl)-4-isopropyloxy-5-m ethoxy-1-oxidopyridinium-2-carboxamide;
GB N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-methoxy-1-oxidopyridinium-2-carboxamide hem ihydrate;
GD N-(2-chlorophenyl)-3-cyclopentyloxy-6-fluoro-4-methoxybenzylamine;
GE N-(2-chlorophenyl)-4-cyclopentyloxy-5-methoxy-2-aminomethylpyridine;
GG trans-2-(2,6-dichlorophenyl)-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)ethene;
GH trans-1-(3-cyclopentyloxy-6-fluoro-4-methoxyphenyl)-2-(2,6-difluorophenyl)ethene;
GI trans-2-(2,6-dichlorophenyl)-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)ethene;
GJ trans-1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(2,6-difluorophenyl)ethene;
GL 1-[(3-cyclopentyloxy-6-fluoro-4-methoxy)phenyl]-2-(pyrid-4-yl)ethane-1,2-dione;
GM 1-(4-cyclopentyloxy-5-methoxypyrid-2-yl)-2-(pyrid-4-yl)ethane-1,2-dione;
GN N-(3,5-dichloropyrid-4-yl)-5-cyclopentyloxy-6-methoxypyridazine-3-carboxamide;
GO N-(3,5-dichloropyridin-4-yl)-4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxamide;
GP N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-difluoromethoxypyridine-2-carboxamide;
GQ N-(3,5-dichloropyrid-4-yl)-4-cyclopentyloxy-5-difluoromethoxy-1-oxidopyridium-2-carboxamide;
GR N-(3,5-dichloro-1-oxido-4-pyridinio)-4-cyclopentyloxy-5-difluoromethoxy-1-oxidopyridium-2-carboxamide;
GS 1-(5-difluoromethoxy-4-(cyclopentyloxy)pyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanone;
GT 1-(5-difluoromethoxy-4-(cyclopentyloxy)-1-oxido-2-pyridium)-2-(3,5-dichloropyridin-4-yl)ethanone;
GU 1-(5-difluoromethoxy-4-(cyclopentyloxy)pyridin-2-yl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone;
GV 1-(5-difluoromethoxy-4-(cyclopentyloxy)-1-oxido-2-pyridium)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone;
GW N-(3,5-dichloropyrid-4-yl)-5,6-dimethoxypyridazine-3-carboxamide; and
GX 1-(5,6-dimethoxypyridazine-3-pyridium)-2-(3,5-dichloropyridin-4-yl)ethanone.
Preferred compounds include A, CC, CD, CE, CF, CG, CH, CI, CJ, CK, CL, CM, CN, CO, CP, CQ, CR, CS, CT, CU, CV, CW, CX, CY, CZ, DA, DB, FF, FG, FH, FI, FJ, FK, FL, FM, FN, FO, FP, FQ, FR, FS, FT, FU, FV, FW, FX, FY, FZ, GA, GB, GN, GO, GP.
The letters A-GX are allocated to compounds for easy reference in this specification.
Compounds of formula I may be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
Thus, compounds of formula I wherein R1, R2, R3, Q1, Q2, Q3, Z1 and 
Z2 are as hereinbefore defined, Z3 represents a xe2x80x94CZNHxe2x80x94 linkage, and Z is oxygen, may be prepared by the reaction of compounds of formula II 
xe2x80x83wherein R1, R2, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and X represents halo, such as bromo or, preferably, chloro, with a compound of the formula III wherein R3 is as hereinbefore defined, preferably in the presence of
R3NH2xe2x80x83xe2x80x83III
xe2x80x83a base such as an alkali metal hydride, such as sodium hydride, or an amine, preferably a tertiary amine, such as triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0xc2x0 C. to the reflux temperature or at the melting point of the reaction mixture.
Alternatively, compounds of formula I wherein R1, R2, R3, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, Z3 represents a xe2x80x94CZNHxe2x80x94 linkage, and Z represents oxygen, may be prepared by the reaction of compounds of formula II as hereinbefore described, with a compound of the formula IV wherein R3
R4CONHR3xe2x80x83xe2x80x83IV
is as hereinbefore defined, and R4 represents an alkyl or cycloalkyl group containing up to 5 carbon atoms, preferably a methyl group, preferably in the presence of a base, for example an alkali metal hydride, such as sodium hydride, or an amine, preferably a tertiary amine, such as triethylamine, in an inert solvent, for example toluene, dimethylformamide, or an ether, such as tetrahydrofuran or diethyl ether, at a temperature from about 0xc2x0 C. to reflux, then a second base, for example an amine, such as piperidine.
Alternatively, compounds of formula I, wherein R1, R2, R3, Q1, Q2 and Q3 are as hereinbefore defined, Z, Z1 and Z2 are oxygen, and Z3 represents a xe2x80x94CZNHxe2x80x94 linkage, may be prepared by the reaction of compounds of formula V hereinafter depicted, wherein R1 and R2 are as hereinbefore defined, Q1, Q2 
and Q3 are independently CH or N and at least one of Q1, Q2 and Q3 is N, with compounds of formula VI wherein R3 and X are as hereinbefore defined,
R3Xxe2x80x83xe2x80x83VI
preferably X is chloro, and preferably the preparation takes place in the presence of a base, for example an alkali metal hydride, such as sodium hydride, an alkali metal alkoxide, such as potassium t-butoxide, an alkali metal hydroxide, such as sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, such as triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0xc2x0 C. to reflux.
Alternatively, compounds of formula 1, wherein R1, R2, R3, Z, Z1, Q1, Q2 and Q3 are as hereinbefore defined, Z3 represents a xe2x80x94CZNHxe2x80x94 linkage, and Z and Z2 are oxygen, may be prepared by the reaction of compounds of formula VII wherein R1, R3, Z, Z1, Q1, Q2 and Q3 are as hereinbefore defined and 
Z3 represents a xe2x80x94CZNHxe2x80x94 linkage, and Z is oxygen, with compounds of the formula VIII wherein R2 is as hereinbefore defined, preferably, X is as
R2Xxe2x80x83xe2x80x83VIII
xe2x80x83hereinbefore defined or p-toluenesulfonate, preferably X is bromo, and preferably the preparation takes place in the presence of a base, for example an alkali metal hydride, such as sodium hydride, an alkali metal hydroxide or carbonate, such as sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, such as. triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0xc2x0 C. to reflux, or by the reaction of the compound of formula VII above with compounds of the formula XXI, as hereinbelow defined in the presence of, for example, diisopropylazodicarboxylate and triphenylphosphine.
Alternatively, compounds of formula 1, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, Z3 represents a xe2x80x94CZCH2xe2x80x94 linkage, and Z represents oxygen, are prepared from compounds of formula IX wherein R1, 
R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, by oxidation by the application or adaptation of known methods. The oxidation is carried out, for example, by reaction with oxalyl chloride and dimethyl sulfoxide, in the presence of a base, preferably a tertiary amine, preferably triethylamine, in an inert solvent such as dichloromethane, at temperatures from about xe2x88x9260xc2x0 C. to about room temperature, preferably at a reduced temperature, or by adaptation of known methods for the preparation of ketone from a secondary alcohol, for example the application of pyridinium dichromate. Alternatively, the oxidation is carried out by reaction with chromium trioxide in the presence of 3,5-dimethylpyrazole.
According to a further feature of the present invention, compounds of formula 1, wherein R1, R2, R3, Z, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, Z3 represents a xe2x80x94CZCH2xe2x80x94 linkage, and preferably those wherein Z represents oxygen, are prepared from compounds of formula X wherein R1, 
R2, Z, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and R5 and R6 represent lower alkyl, such as methyl, groups, by coupling with compounds of the formula XI wherein R3 is as hereinbefore defined, in the presence of a
xe2x80x83R3CH3xe2x80x83xe2x80x83XI
xe2x80x83strong base such as lithium diisopropylamide (usually prepared in situ from n-butyl lithium and diisopropylamine), preferably at a low temperature.
Alternatively, compounds of formula I, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, Z3 represents a xe2x80x94CZCH2xe2x80x94 linkage, and Z represents oxygen, are prepared from compounds of formula XII wherein R1, 
R2, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, and R7 is alkyl, cycloalkyl or aralkyl containing up to 8 carbon atoms, by coupling with compounds of the formula XI above, wherein R3 is as hereinbefore defined, in the presence of a strong base, such as an alkali metal amide or alkyl, for example n-butyl lithium or lithium diisopropylamide (usually prepared in situ from butyl lithium and diisopropylamine), in an inert solvent, for example cyclohexane or an ether, such as tetrahydrofuran or diethyl ether, at a temperature from about xe2x88x9278xc2x0 C. to about room temperature.
According to a further feature of the present invention, compounds of formula I, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and Z3 represents a xe2x80x94CH2xe2x80x94NHxe2x80x94 linkage are prepared by the reaction of compounds of formula XIII wherein R1, R2, Z1, Z2, Q1, Q2 and Q3 are as 
hereinbefore defined, with compounds of formula III above, wherein R3 is as hereinbefore defined, followed by reduction with a compound such as sodium cyanoborohydride. This process is especially suitable for compounds wherein R3 represents an optionally substituted phenyl or naphthyl group.
According to a further feature of the present invention, compounds of formula I, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and Z3 represents a xe2x80x94CH2xe2x80x94NHxe2x80x94 linkage are prepared by the reaction of compounds of formula XIV wherein X, R1, R2, Z1, Z2, Q1, Q2 and Q3 are as 
hereinbeforedefined, and X is preferably bromo, with compounds of formula III above, wherein R3 is as hereinbefore defined, preferably in the presence of a base such as sodium hydride. This process is especially suitable for compounds wherein R3 represents an optionally substituted heteroaryl group.
According to a further feature of the present invention, compounds of formula I, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and Z3 represents a trans xe2x80x94CHxe2x95x90CHxe2x80x94 linkage are prepared by the reaction of compounds of formula XII above, wherein R1, R2, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, with the reaction product of a compound of the formula XV wherein R3 is as hereinbefore defined, R8 represents
(R8PCH2R3)+(X)xe2x88x92xe2x80x83xe2x80x83XV
an aryl, such as phenyl group, and X represents halo, preferably bromo, with a base such as an alkali metal alkoxide, for example potassium t-butoxide. The reaction is preferably carried out in a solvent such as tetrahydrofuran.
According to a further feature of the present invention, compounds of formula I, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and Z3 represents a xe2x80x94CF2xe2x80x94Oxe2x80x94 linkage are prepared by the reaction of compounds of formula XVI, wherein R1, R2, Z1, Z2, Q1, Q2 and Q3 are wherein 
R1, R2, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, with compounds of the formula XVII wherein R3 is as hereinbefore defined, preferably with the aid
R3OHxe2x80x83xe2x80x83XVII
xe2x80x83of a base such as sodium hydride, preferably in a solvent such as tetrahydrofuran.
According to a further feature of the present invention, compounds of formula 1, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and Z3 represents a xe2x80x94CH2xe2x80x94Oxe2x80x94 linkage are prepared by the reaction of compounds of formula XVIII wherein R1, R2, Z1, Z2, Q1, Q2 and Q3 are as 
hereinbefore defined, with compounds of the formula VI hereinbefore, wherein R3 and X are as hereinbefore defined, preferably with the aid of a base such as an alkali metal alkoxide, such as potassium t-butoxide. The reaction is preferably carried out in a solvent such as tetrahydrofuran.
According to a further feature of the present invention, compounds of formula I, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and Z3 represents a xe2x80x94CH2xe2x80x94Oxe2x80x94 linkage are prepared by the reaction of compounds of formula XIV above, wherein R1, R2, Z1, Z2, Q1, Q2, Q3 and X are as hereinbefore defined, with compounds of formula XVII above, wherein R3 is as hereinbefore defined, preferably with the aid of a base such as an alkali metal alkoxide, such as potassium t-butoxide.
According to a further feature of the present invention, compounds of formula I, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and Z3 represents a xe2x80x94COxe2x80x94COxe2x80x94 linkage are prepared by the oxidation of compounds of formula IX above, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, for example by reaction with pyridinium dichromate, preferably in a solvent such as dichloromethane. This reaction is particularly suitable for compounds wherein R3 represents a heteroaryl, preferably an optionally substituted pyridyl, group.
According to a further feature of the present invention, compounds of formula I, wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined and Z3 represents a xe2x80x94CH2xe2x80x94Sxe2x80x94 linkage are prepared by the reaction of compounds of formula XIV above, wherein X, R1, R2, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, with compounds of the formula XX wherein R3 is
R3xe2x80x94SHxe2x80x83xe2x80x83XX
as hereinbefore defined, preferably with the aid of a base such as an alkali metal carbonate, such as potassium carbonate. Compounds of formula I wherein Z3 is xe2x80x94CH2xe2x80x94Sxe2x80x94, preferably wherein Z, Z1 and Z2 each represent oxygen, and R2 is alkyl or cycloalkyl, may then be oxidized to the corresponding sulphinyl or sulphonyl group. For example, the oxidation to xe2x80x94CH2xe2x80x94SOxe2x80x94 can be carried out by means of potassium hydrogen peroxomonosulfate in a medium such as aqueous methanol. For example, the oxidation to xe2x80x94CH2xe2x80x94SO2xe2x80x94 can be carried out by means of sodium iodate in a medium such as aqueous methanol.
According to another feature of the invention, compounds of formula I wherein R1, R2, R3, Z1, Z3, Q1, Q2 and Q3 are as hereinbefore defined, and R2 represents cyclosulphonylalkyl, cyclosulphinylalkyl, cyclosulphonylalkenyl or cyclosulphinylalkenyl, are prepared by oxidizing the corresponding compounds of formula I wherein R2 represents cyclosulphonylalkyl or cyclosulphinylalkyl. For example, the oxidation to sulphinyl can be carried out by means of potassium hydrogen peroxomonosulfate in a medium such as aqueous methanol. For example, the oxidation to sulphonyl can be carried out by means of sodium iodate in a medium such as aqueous methanol.
As another example, compounds of formula I wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, and Z3 represents a cis xe2x80x94Cxe2x95x90Cxe2x80x94 isomer linkage are prepared by the action of ultraviolet radiation upon the trans-isomer.
As another example, compounds of formula I wherein R1, R2, R3, Z1, Z1, Q1, Q2 and Q3 are as hereinbefore defined, and Z3 contains a xe2x80x94CSxe2x80x94 moiety, are prepared from compounds of formula I wherein R1, R2, R3, Z1, Z2, Q1, Q2 and Q3 are as hereinbefore defined, and Z3 contains a xe2x80x94COxe2x80x94 moiety, by reaction with phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, preferably in a solvent such as pyridine or toluene, and preferably at a temperature from about 0xc2x0 C. to reflux.
As another example, compounds of formula I wherein R3 is as hereinbefore defined and contains an alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl group, R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, are prepared by oxidising the corresponding compounds of formula I wherein R3 is as hereinbefore defined and contains an alkylthio or arylthio group, R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, preferably wherein Z, Z1 and Z2 each represent oxygen, and R2 is alkyl or cycloalkyl, preferably with a peroxyacid, such as 3-chloroperbenzoic acid, preferably in an inert solvent, such as dichloromethane, preferably at about room temperature. Alternatively, the oxidation is carried out by reaction with a peroxomonosulfate, such as potassium peroxomonosulfate, conveniently in a solvent such as methanol, buffered to about pH 5, at temperatures from about 0xc2x0 C. to about room temperature. This latter method is preferred for compounds containing an acid-labile group, such as those wherein the moiety R2 is unsaturated, such as a cyclopent-2-enyloxy group.
As another example, compounds of formula I wherein R3 is as hereinbefore defined and contains a hydroxymethyl group, and R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, are prepared by the reduction of the corresponding compounds of formula I wherein R3 is as hereinbefore defined and contains an aryloxycarbonyl or, preferably, alkoxycarbonyl group, R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, and Z is preferably oxygen, preferably by means of reacting an alkali metal borohydride, preferably in an inert solvent, such as tetrahydrofuran, preferably at about room temperature.
As another example, compounds of formula I wherein R3 is as hereinbefore defined and contains a formyl group, and R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, are prepared by the oxidising the corresponding compounds of formula I wherein R3 is as hereinbefore defined and contains a hydroxymethyl group, R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, and Z preferably being an oxygen atom, for example with oxalyl chloride and dimethyl sulfoxide, in a solvent such as dichloromethane, and preferably at a temperature lower than about xe2x88x9265xc2x0 C., or, preferably, by reaction with a complex of sulfur trioxide with an amine such as pyridine, preferably in the presence of an amine such as triethylamine, preferably at about room temperature.
As another example, compounds of formula I wherein R3 is as hereinbefore defined and contains an amino group, and R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, are prepared by the reducing the corresponding compounds of formula I wherein R3 is as hereinbefore defined and contains a nitro group, R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, and Z is preferably oxygen, preferably with iron in acidic conditions, such as in acetic acid, preferably at or above room temperature, more especially at the reflux temperature. Alternatively the reduction are carried out by reaction with hydrazine hydrate in the presence of ferric chloride and activated carbon, conveniently in a solvent such as methanol, at temperatures from about 25xc2x0 C. to about 80xc2x0 C. This latter method is preferred for compounds containing an acid-labile group, such as those wherein the moiety R2 is unsaturated, such as a cyclopent-2-enyloxy group.
As another example, compounds of formula I wherein R3 is as hereinbefore defined and contains an alkanoylamino or aroylamino group, and R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, are prepared from compounds of formula I wherein R3 is as hereinbefore defined and contains an amino group, R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, and Z is preferably oxygen, preferably by means of reaction with the appropriate acid halide or acid anhydride in the presence of a tertiary base, such as triethylamine, optionally in an inert solvent, and preferably at a temperature from about 0xc2x0 C. to reflux.
Compounds of formula I wherein R3 is as hereinbefore described, including an azaheteroaryl group containing one or more nitrogen ring atoms, preferably imine (xe2x95x90Nxe2x80x94), and R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, may be converted to the corresponding compounds wherein a nitrogen atom of the azaheteroaryl moiety is oxidised to an N-oxide, R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are hereinbefore defined, and preferably Z, Z1 and Z2 each represent oxygen, and R2 is alkyl or cycloalkyl, preferably by reacting a peracid, for example peracetic acid in acetic acid or m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature. Preferably wherein Z, Z1 and Z2 each represent oxygen, and R2 is an oxidised cyclothioalkyl, such as cyclosulphinyl or sulphonyl, the reaction is carried out at a temperature from about room temperature to reflux, preferably at a reduced temperature. Alternatively, the oxidation is carried out by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures from about room temperature to about 60xc2x0 C. This latter method is preferred for compounds containing an acid-labile group, such as those wherein the moiety R2 contains a carbon-carbon double bond between its beta- and gamma-carbon atoms, such as a cyclopent-2-enyloxy group.
Compounds of formula I wherein R3 represents an azaheteroaryl group containing a nitrogen ring atom as an N-oxide, and R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, may be converted to the corresponding compounds wherein Q1, Q2 or Q3 as a nitrogen atom is oxidised to an N-oxide moiety, R1, R2, Z, Z1, Z2 and Z3 are hereinbefore defined, and preferably wherein Z, Z1 and Z2 each represent oxygen, and R2 is alkyl or cycloalkyl, by reacting a peracid, for example m-chloroperoxy-benzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
Compounds of formula I wherein R3 represents a azaheteroaryl group containing one or more nitrogen ring atoms, preferably imine (xe2x95x90Nxe2x80x94), and R1, R2, Q1, Q2, Q3, Z, Z1, Z2 and Z3 are as hereinbefore defined, may be converted to the corresponding compounds wherein a nitrogen atom of the azaheteroaryl moiety is oxidised to an N-oxide, wherein Q1, Q2 or Q3 as a nitrogen atom is oxidised to an N-oxide moiety, R1, R2, Z, Z1, Z2 and Z3 are hereinbefore defined, and preferably wherein Z, Z1 and Z2 each represent oxygen, and R2 is alkyl or cycloalkyl, preferably by reacting a peracid, for example m-chloroperoxybenzoic acid in an inert solvent such as dichloromethane, at a temperature from about room temperature to reflux, preferably at elevated temperature.
Compounds of formula I wherein R3 represents an azaheteroaryl group containing a nitrogen ring atom as an N-oxide, Q1, Q2 or Q3 as a nitrogen atom is oxidised to an N-oxide moiety, and R1, R2, Z, Z1, Z2 and Z3 are as hereinbefore defined, may be converted to the corresponding compounds wherein R3 represents an azaheteroaryl group containing one or more nitrogen ring atoms, preferably imine (xe2x95x90Nxe2x80x94), Q1, Q2 or Q3 as a nitrogen atom is oxidised to an N-oxide moiety, R1, R2, Z, Z1, Z2 and Z3 are hereinbefore defined, preferably by reacting in a deoxygenating system, for example diphosphorus tetraiodide in an inert solvent, such as dichloromethane, preferably at room temperature, or with a chlorotrialkylsilane, preferably chlorotrimethylsilane, in the presence of an alkali metal iodide, e.g potassium iodide, and zinc, in an inert solvent, for example acetonitrile, at temperatures from about 0xc2x0 C. to about room temperature, preferably at reduced temperature.
For example, compounds of formula I wherein R1 is as hereinbefore defined and is substituted by fluorine on a carbon atom thereof alpha to the attachment of R1to Z1 as sulfur, or wherein R2 is as hereinbefore defined and is substituted by fluorine on a carbon atom thereof alpha to the attachment of R2 to Z2 as sulfur, and Q1, Q2, Q3, R3 and Z3 as hereinbefore defined, are prepared by reacting xenon difluoride with corresponding compounds of formula I wherein said alpha-carbon atoms carry hydrogen atoms instead of said fluorine atoms. The reaction is conveniently carried out in a solvent, such as dichloromethane, in the presence of a molecular sieve, and in an inert atmosphere, at a low temperature, such as at about 0xc2x0 C. Alternatively, compounds of formula I wherein R1 is a difluoromethyl group may be prepared by reacting a compound of formula I or precursor wherein Z1 is hydroxy or thiol with HCBrF2 in the presence of a strong base in an inert solvent.
As another example, compounds of formula I wherein R3 represents a heteroaryl group containing one or more nitrogen ring atoms but carrying no halogen substituents, and R1, R2, R3, Z1, Z2, Z3, Q1, Q2 and Q3 are as hereinbefore defined, are prepared by the reduction of the corresponding compounds of formula I wherein R3 does carry one or more halo, such as chloro, substituents, for example by means of ammonium formate in the presence of a palladium catalyst.
The compounds of the present invention are useful in the form of the free base or acid or in the form of a pharmaceutically acceptable salt thereof. All forms are within the scope of the invention.
Where the compound of the present invention is substituted with a basic moiety, acid addition salts are formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free base form. The acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the patient in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on TNF and PDE inherent in the free base are not vitiated by side effects ascribable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as sources of the free base form even if the particular salt, per se, is desired only as an intermediate product as, for example, when the salt is formed only for purposes of purification, and identification, or when it is used as intermediate in preparing a pharmaceutically acceptable salt by ion exchange procedures. Pharmaceutically acceptable salts within the scope of the invention are those derived from the following acids: mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like. The corresponding acid addition salts comprise the following: hydrohalides, such as hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate, acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate, propionate, succinate, fumarate, maleate, methylene-bis-beta-hydroxynaphthoates, gentisates, mesylates, isethionates and di-p-toluoyltartratesmethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate, respectively.
According to a further feature of the invention, acid addition salts of the compounds of this invention are prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds of this invention are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The acid addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their acid addition salts by treatment with an alkali, such as aqueous sodium bicarbonate solution or aqueous ammonia solution.
Where the compound of the invention is substituted with an acidic moiety, base addition salts may be formed and are simply a more convenient form for use; and in practice, use of the salt form inherently amounts to use of the free acid form. The bases which can be used to prepare the base addition salts include preferably those which produce, when combined with the free acid, pharmaceutically acceptable salts, that is, salts whose cations are non-toxic to the animal organism in pharmaceutical doses of the salts, so that the beneficial inhibitory effects on TNF and PDE inherent in the free acid are not vitiated by side effects ascribable to the cations. Pharmaceutically acceptable salts, including for example alkali and alkaline earth metal salts, within the scope of the invention are those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and the like.
Metal salts of compounds of the present invention may be obtained by contacting a hydride, hydroxide, carbonate or similar reactive compound of the chosen metal in an aqueous or organic solvent with the free acid form of the compound. The aqueous solvent employed may be water or it may be a mixture of water with an organic solvent, preferably an alcohol such as methanol or ethanol, a ketone such as acetone, an aliphatic ether such as tetrahydrofuran, or an ester such as ethyl acetate. Such reactions are normally conducted at ambient temperature but they may, if desired, be conducted with heating.
Amine salts of compounds of the present invention may be obtained by contacting an amine in an aqueous or organic solvent with the free acid form of the compound. Suitable aqueous solvents include water and mixtures of water with alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, nitrites such as acetonitrile, or ketones such as acetone. Amino acid salts may be similarly prepared.
The base addition salts of the compounds of this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds of the invention can be regenerated from their base addition salts by treatment with an acid, such as hydrochloric acid.
As will be self-evident to those skilled in the art, some of the compounds of this invention do not form stable salts. However, acid addition salts are most likely to be formed by compounds of this invention wherein R3 represents a nitrogen-containing heteroaryl group and/or wherein R3 contains an amino group as a substituent. Preferable acid addition salts of the compounds of the invention are those wherein R2 is other than an acid labile group.
As well as being useful in themselves as active compounds, salts of compounds of the invention are useful for the purposes of purification of the compounds, for example by exploitation of the solubility differences between the salts and the parent compounds, side products and/or starting materials by techniques well known to those skilled in the art.
It will be apparent to those skilled in the art that certain compounds of formula I can exhibit isomerism, for example geometrical isomerism and optical isomerism. Optical isomers include compounds of the invention having asymmetric centers that may independently be in either the R or S configuration. Geometrical isomers include the cis and trans forms of compounds of the invention having alkenyl moieties. Individual geometrical isomers, stereoisomers and mixtures thereof are within the scope of the present invention.
Such isomers can be separated from their mixtures, by the application or adaptation of known methods, for example chromatographic techniques and recrystallization techniques, or they are separately prepared from the appropriate isomers of their intermediates, for example by the application or adaptation of methods described herein.
The starting materials and intermediates are prepared by the application or adaptation of known methods, for example methods as described in the Reference Examples or their obvious chemical equivalents.
For example, compounds of formula 11, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, are prepared from compounds of formula XIX wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, by the 
application or adaptation of known methods for the preparation of acid halides from carboxylic acids. For example, whenthe moiety X in a compound of formula II represents a chloro, the reaction may be carried out by means of thionyl chloride or, preferably, oxalyl chloride in the presence of triethylamine, or as prepared by adaptation of the procedures described by K. R. Reistad et al., Acta. Chemica. Scandanavica B, 28, 667-72 (1974), incorporated herein by reference.
Compounds of formula XIX, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, are prepared by the oxidation of compounds of formula XIII above, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, for example by means of reaction with potassium permanganate, or with a mixture of sulfamic acid and sodium chlorite in acetic acid, or with sodium chlorite in the presence of sodium dihydrogen phosphate.
According to a further feature of the invention, compounds of formula XIX, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, are prepared by the oxidation of compounds of formula XVIII, 
by adaptation of known methods for the preparation of carboxylic acids from primary alcohols, for example potassium permanganate in water or a mixture of water and inert organic solvent, e.g dichloromethane, in the presence of a phase transfer catalyst, such as aliquat 336, at about room temperature to reflux. Alternatively, the compound of formula XVIII is oxidized as described by H. C. Beyerman, Receueil, 77, 249-57, (1958), incorporated herein by reference.
Compounds of formula XIII, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, are prepared from compounds of formula XX 
wherein R1, Q1, Q2, Q3 and Z1 are as hereinbefore defined, by reaction with compounds of formula VIII wherein R2 and X are as hereinbefore defined, and X is preferably bromo, preferably in the presence of a base, for example an alkali metal hydride, such as sodium hydride, an alkali metal hydroxide or carbonate, such as sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, such as triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0xc2x0 C. to reflux, or
xe2x80x83R2OHxe2x80x83xe2x80x83XXI
as hereinbefore defined, preferably in the presence of a compound such as diisopropyl azodicarboxylate and triphenylphosphine.
Alternatively compounds of formula XIX above, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, are prepared by the hydrolysis of compounds of formula XII above, wherein R1, R2, R7, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, for example by reaction with a base, such as an aqueous alkali metal hydroxide, alkali metal carbonate or bicarbonate, such as potassium hydroxide or potassium carbonate, in an inert co-solvent such as methanol at a temperature from about room temperature to reflux, and then with an aqueous acid such as hydrochloric acid or acetic acid.
Compounds of formula XII above, wherein R1, R2, R7, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, are prepared from compounds of formula XXII 
by reaction with compounds of the formula XXI above, wherein R2 is as wherein R1, R7, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, preferably in the presence of diisopropyl azodicarboxylate and triphenylphosphine.
Alternatively, compounds of formula XII above, as hereinbefore defined, can be prepared from compounds of formula XXII above, as hereinbefore defined, by reaction with compounds of the formula VIII above, as hereinbefore defined, in the presence of base, for example an alkali metal hydride, such as sodium hydride, a tertiary amine, such as triethylamine, or preferably an alkali metal carbonate or hydroxide, such as sodium carbonate or hydroxide, or in the presence of a transition metal carbonate, such as silver carbonate, optionally in an inert solvent, such as dimethylformamide or tetrahydrofuran, preferably at a temperature from about 0xc2x0 C. to about 80xc2x0 C.
Compounds of formula IX above, wherein R1, R2, R3, Q1, Q2, Q3, Z1, Z2 and Z3 are as hereinbefore defined, are prepared by the reaction of compounds of formula XII above, wherein R1, R2, Q1, Q2, Q3, Z1 and Z1 are as hereinbefore defined, with compounds of the formula XI above, wherein R3 is as hereinbefore defined, in the presence of a base such as an alkali metal amide or alkyl, for example n-butyllithium or lithium diisopropylamide, in an inert solvent, for example cyclohexane or an ether, such as tetrahydrofuran or diethyl ether, at a temperature from about xe2x88x9278xc2x0 C. to about room temperature, preferably at a reduced temperature.
Compounds of formula XVI above, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, are prepared by the reaction of bromine in carbon tetrachloride and ultraviolet radiation on the corresponding compounds wherein the bromodifluormethyl moiety is xe2x80x94CHF2, which themselves are prepared by the action of sulfur tetrafluoride and hydrofluoric acid on compounds of formula XII above, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, in the presence of pyridine.
Compounds of formula XIII above, wherein R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, are prepared from compounds of formula XVIII above, R1, R2, Q1, Q2, Q3, Z1 and Z2 are as hereinbefore defined, by a Swern oxidation using a mixture of dimethyl sulphoxide and oxalyl chloride in the presence of a base, preferably a tertiary amine, preferably triethylamine, in an inert solvent e.g dichloromethane, at temperatures from about xe2x88x9260xc2x0 C. to about room temperature, or preferably using activated manganese dioxide in an inert solvent, for example dichloromethane or diethyl ether, preferably at about room temperature.
Compounds of formula XXII above, wherein R1, R7, Q1, Q2, Q3 and Z1 are as hereinbefore defined, and Z2 represents an oxygen atom are prepared from compounds of formula XXIII, wherein R1, R7, Q1, Q2, Q3 and Z1 
as hereinbefore described, by diazotisation of the amino group with an alkali metal nitrite, such as sodium nitrite, under aqueous acid conditions, such as aqueous hydrochloric acid, at room temperature or below, preferably at about 0xc2x0 C. The diazo species is isolated by the addition of an alkali metal salt which stabilises the diazonium salt, such as sodium tetrafluoroborate, at room temperature or below, preferably at about 0xc2x0 C. The resulting stabilised diazonium salt is then decomposed under acid conditions, such as trifluoroacetic acid, at elevated temperature, such as boiling point of the acid.
Alternatively, compounds of formula XXII above, wherein R1, R7, Q1, Q2, Q3 and Z1 are as hereinbefore defined, and Z2 represents a sulphur atom are prepared from compounds of formula XXIII above, wherein R1, R7, Q1, Q2, Q3 and Z1 are as hereinbefore defined, by diazotisation of the amino group with an alkali metal nitrite, such as sodium nitrite, under aqueous acid conditions, such as aqueous hydrochloric acid, at room temperature or below, preferably at about 0xc2x0 C. The diazo species is isolated by the addition of an alkali metal salt which stabilises the diazonium salt, such as sodium tetrafluoroborate, at room temperature or below, preferably at about 0xc2x0 C. The resulting stabilised diazonium salt is then reacted with a sulphydryl anion, such as sodium hydrogen sulphide.
Compounds of formula XXIII above, wherein R1, R7, Q1, Q2, Q3 and Z1 are as hereinbefore defined, are prepared from compounds of formula XXIV 
wherein R1, R7, Q1, Q2, Q3 and Z1 are as hereinbefore defined, by reduction of the nitro group with hydrogen and a metal catalyst, such as 5% palladium supported on carbon, in an inert solvent, such as ethyl acetate, or using a dissolving metal reduction, for example tin or zinc, preferably iron, in aqueous acid, for example hydrochloric acid, or preferably acetic acid, optionally with an inert co-solvent, for example ethanol, at a temperature from about room temperature to reflux, preferably at elevated temperature.
Compounds of formula XXIV above, wherein R1, R7, Q1, Q2, Q3 and Z1 are as hereinbefore defined, are prepared from compounds of formula XXV 
wherein R7, Q1, Q2 and Q3 are as hereinbefore defined (prepared by the method of Berrie et al. J. Chem. Soc. 2590-4 (1951), Ger. Offen. 2,130,311 and U.S. Pat. No. 3,903,146, incorporated herein by reference), by reaction with compounds of formula XXVI, wherein Z1 and R1 are as hereinbefore defined,
R1Z1Mxe2x80x83xe2x80x83XXVI
and M represents an alkaline metal, such as sodium, in an alcohol, such as methanol where Z1 is oxygen, or inert solvent, for example where Z1 is sulphur, at room temperature or up to 80xc2x0 C., preferably at room temperature.
Alternatively, compounds of formula XII above, wherein Z1, R1, and R7 are as hereinbefore defined, and Q1 and Q2 are CH, and Q3 is nitrogen are prepared by reaction of compounds of formula XXVII, wherein X, Z1, R1 and R7
are as hereinbefore defined, with compounds of formula XXVI above, wherein Z2, R2 and M are as hereinbefore defined, preferably in the presence of a base, for example alkali metal or alkali metal hydride, such as sodium or sodium hydride, without co-solvent or in the presence of an inert solvent, such as tetrahydrofuran, from about room temperature to reflux, preferably at about room temperature.
Compounds of formula XXVII above, wherein Z1, R1 and R7 are as defined hereinbefore, are prepared by the reaction of compounds of formula XXVIII, wherein X, Z1 and R1 are as hereinbefore defined, with compounds 
of formula XXIX, wherein R7 is as hereinbefore defined, preferably using the
R7OHxe2x80x83xe2x80x83XXIX
compound of XXIX as the solvent, from about room temperature to reflux.
Compounds of formula XXVIII above, wherein X, R1 and Z1 are as hereinbefore defined, are prepared from compounds of formula XXX, wherein 
X, R1 and Z1 are as hereinbefore defined, a by adaptation of procedures described by K. R. Reistad et al., Acta. Chemica. Scandanavica B, 28, 667-72 (1974), incorporated herein by reference.
Compounds of formula XXX above, wherein X, R1 and Z1 are as hereinbefore defined, are prepared by the reaction of compounds of formula XXXI, wherein X and Z1 is as hereinbefore defined, with compounds of 
formula XXXII, wherein R1 is as hereinbefore defined, by adaptation of
xe2x80x83(R1)2SO4xe2x80x83xe2x80x83XXXII
procedures described by K. R. Reistad et al., Acta. Chemica. Scandanavica B, 28, 667-72 (1974), incorporated herein by reference.
Alternatively, compounds of formula XVIII above, wherein Z1 represents oxygen, Z2 represent oxygen or sulphur atoms, Q1 and Q3 represent CH, and Q2 represents a nitrogen atom, and R1 and R2 are as hereinbefore defined are prepared from compounds of formula XXXIII, wherein R1, R2 and Z2 are as 
hereinbefore defined, and P represents a protecting group, such as a silyl group, for example t-butyldimethylsilyl, or a trityl group, by reaction with an excess or a catalytic quantity of aqueous acid, for example formic acid, trifluoroacetic acid or acetic acid, neat or in the presence of a co-solvent, for example ethyl acetate, at a temperature from about room temperature to about 100xc2x0 C.
Compounds of formula XXXIII above, R1, R2, Z2 and P are as hereinbefore defined, are prepared by the reaction of compounds of formula XXXIV, wherein Y represents P1 or R1, P1 represents a protecting group, such 
as benzyl, and R1, Z2 and P are as hereinbefore defined, (1) where Y and Z2 of XXXIV represent respectively R1 and an oxygen atom, with compounds of formula XXI, wherein R2 is as hereinbefore defined, in the presence of a dialkyl diazodiarboxylate, for example diisopropyldiazodicarboxylate, and a phosphine, preferably triarylphosphine, such as triphenylphosphine, in an inert solvent, for example toluene or an ether, such as tetrahydrofuran or diethyl ether, at a temperature from about xe2x88x9220xc2x0 C. to reflux, or (2) where Y and Z2 of XXXIV represent respectively R1 and a sulphur atom, with compounds of formula VIII above, wherein R2 and X are as hereinbefore defined, and X is preferably bromo, preferably in the presence of a base, for example an alkali metal hydride, such as sodium hydride, an alkali metal hydroxide or carbonate, such as sodium hydroxide or carbonate, or an amine, preferably a tertiary amine, such as triethylamine or pyridine, optionally in an inert solvent, for example dichloromethane, dimethylformamide, or an ether, such as diethyl ether or tetrahydrofuran, preferably at a temperature from about 0xc2x0 C. to reflux, or (3) where Y of XXXIV represents P1, a protecting group as hereinbefore defined, and Z2 of XXXIV represents an oxygen or sulphur atom, then XXXIV is treated as in procedure (1) or (2) herein to prepare compounds of formula XXXV, wherein Y is P1, and P, P1, Z2 and R2 are as herein beforefore defined, 
that are then selectively deprotected to remove P1 as a benzyl group, for example by hydrogenolysis in the presence of a supported metal catalyst, such as 5% palladium on charcoal, in an inert solvent, for example ethyl acetate, or preferably ethanol to yield compounds of formula XXXVI, wherein p, Z2 and R2 
are as hereinbefore defined, that are then alkylated with compounds of formula XXXVII, wherein R1 and X are hereinbefore defined, in the presence of a base,
R1Xxe2x80x83xe2x80x83XXXVII
for example an amine, such as 1,8-diazabicyclo[5.4.0]undec-7-ene, or preferably an alkali metal carbonate, such as potassium carbonate, in an inert solvent, for example dimethylformamide, at a temperature from about 0xc2x0 C. to about 120xc2x0 C.
Compounds of formula XXXIV above, wherein Y, Z2 and P are as hereinbefore defined, are prepared by the reaction of compounds of formula XXXVIII, wherein Y is as hereinbefore defined, and Z2 represents an oxygen 
atom, with compounds of formula XXXIX, wherein P and X are as
PXxe2x80x83xe2x80x83XXXIX
hereinbefore defined, preferably in the presence of base, for example an amine, preferably a tertiary amine, for example triethylamine or preferably 4-dimethylaminopyridine, in an inert solvent, for example dimethylformamide or tetrahydrofuran, at from about room temperature to about 120xc2x0 C., preferably from about 60xc2x0 C. to about 100xc2x0 C., and the protected product is optionally converted to the corresponding protected product wherein Z2 is sulphur, with phosphorus pentasulfide or 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, preferably in a solvent such as pyridine or toluene, and preferably at a temperature from about 0xc2x0 C. to reflux.
Compounds of formula XXXVIII above, wherein Z2 represents an oxygen atom, and Y is as hereinbefore defined, are prepared from compounds of formula XXXX, wherein Y is as hereinbefore defined, by adaptation of the 
procedures described by H. C. Beyerman, Receueil, 77, 249-57, (1958) and European Patent 204207 (20/05/86), incorporated herein by reference.
Compounds of formula XXXX wherein Y is as hereinbefore defined, are prepared by the reaction of compounds of formula XXXXI, with compounds 
of formula XXXII above, wherein R1 is as hereinbefore defined, by adaptation of the alkylation procedure described by H. C. Beyerman, Receueil, 77, 249-57, (1958) and European Patent 204207 (20/05/86), incorporated herein by reference.
Compounds of formula XII above, wherein Z1 and Z2 represent an oxygen atoms, Q1 and Q3 represent CH, Q2 represents N, and R1, R2 and R7 are as hereinbefore defined are prepared by the reaction of compounds of formula XXXXII, wherein Z2 represents an oxygen atom, and R1 and R7 are as 
hereinbefore defined, with compounds of formula XXI above, wherein R2 is as hereinbefore defined, in the presence of a dialkyl diazodiarboxylate, for example diisopropyldiazodicarboxylate, and a phosphine, preferably triarylphosphine, such as triphenylphosphine, in an inert solvent, for example toluene or an ether, such as tetrahydrofuran or diethyl ether, at a temperature from about xe2x88x9220xc2x0 C. to reflux.
Compounds of formula XXXXII above, wherein Z2 represents an oxygen atom, and R1 and R7 are as hereinbefore defined, are prepared by the reaction of compounds of formula XXXXIII, wherein R1 and Z2 are as 
hereinbefore defined, with compounds of formula XXIX,wherein R7 is as hereinbefore defined, in the presence of an acid, preferably a mineral acid, for example sulphuric acid, or preferably hydrogen chloride, at a temperature from about 0xc2x0 C. to reflux, preferably at an elevated temperature.
Compounds of formula XXXXIII above, wherein R1 and Z2 are as hereinbefore defined, are prepared from compounds of formula XXXVIII above, wherein Y is R1, Z2 represents an oxygen atom, and R1 is as hereinbefore defined, by adaptation of the procedure described by H. C. Beyerman, Receueil, 77, 249-57, (1958), incorporated herein by reference.
Alternatively, compounds of formula XVIII above, wherein Q1 and Q2 are N, Q3 is CH, R1 R2 are as hereinbefore defined, and Z1 and Z2 represent oxygen atoms, are prepared from compounds of formula XXXXIV, wherein R1, 
R2, and R4 are as hereinbefore defined, by reaction with aqueous alkali metal hydroxide or carbonate, such as potassium hydroxide or preferably potassium carbonate, in an inert co-solvent, such as methanol, at a temperature from about room temperature to reflux.
Compounds of formula XXXXIV above, wherein R1, R2, and R4 are as hereinbefore defined, are prepared from compounds of formula XXXXV, 
wherein R1 and R2 are as hereinbefore defined (prepared by adaptation of the method of M. Ogata and H. Kano, J. Heterocyclic Chem., 11, 29-35, (1963), incorporated herein by reference), by reaction with compounds of the formula XXXXVI, wherein R4 is as hereinbefore defined, preferably a
(R4CO)2Oxe2x80x83xe2x80x83XXXXVI
methyl group, using compound XXXXVI as solvent at about room temperature to reflux, preferably at elevated temperature.